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3-(2-oxoethylidene)indolin-2-one derivatives activate Nrf2 and inhibit NF-κB: potential candidates for chemoprevention.

Authors
  • Nagle, Amrita A1
  • Reddy, Shridhivya A
  • Bertrand, Helene
  • Tajima, Hisashi
  • Dang, Truong-Minh
  • Wong, Siew-Cheng
  • Hayes, John D
  • Wells, Geoffrey
  • Chew, Eng-Hui
  • 1 Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543 (Republic of Singapore). , (Singapore)
Type
Published Article
Journal
ChemMedChem
Publisher
Wiley (John Wiley & Sons)
Publication Date
Aug 01, 2014
Volume
9
Issue
8
Pages
1763–1774
Identifiers
DOI: 10.1002/cmdc.201402038
PMID: 24819554
Source
Medline
Keywords
License
Unknown

Abstract

Induction of cytoprotective phase 2 enzymes through inhibition of Keap1, a repressor of transcription factor Nrf2, is a cancer-prevention strategy. Compounds that elicit antiinflammatory and cytoprotective effects are promising candidates for chemoprevention. Novel analogues of 1-methyl-3-(2-oxopropylidene)indolin-2-one ('supercinnamaldehyde'; SCA) were synthesized, and their abilities to induce cytoprotective responses through Nrf2 induction and to suppress inflammatory responses were examined. 1-Methyl-3-(2-oxo-2-phenylethylidene)indolin-2-one (6) was identified as the lead compound. The compounds showed induction of Nrf2-dependent phase 2 enzymes in Keap1+/+ mouse embryonic fibroblasts (MEFs), which was abrogated in Keap1-/- MEFs. The compounds also displayed a suppressive effect on NF-κB signaling that was at least partly responsible for inhibition of lipopolysaccharideinduced inflammatory responses. These SCA analogues exhibited cytoprotective and anti-inflammatory activities and may be developed further as chemopreventive agents.

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